Ficolin-A/2 Aggravates Severe Lung Injury through Neutrophil Extracellular Traps Mediated by Gasdermin D-Induced Pyroptosis.
Am J Pathol
; 194(6): 989-1006, 2024 06.
Article
en En
| MEDLINE
| ID: mdl-38442803
ABSTRACT
Neutrophil extracellular traps (NETs) and pyroptosis are critical events in lung injury. This study investigated whether ficolin-A influenced NET formation through pyroptosis to exacerbate lipopolysaccharide (LPS)-induced lung injury. The expression of ficolin-A/2, NETs, and pyroptosis-related molecules was investigated in animal and cell models. Knockout and knockdown (recombinant protein) methods were used to elucidate regulatory mechanisms. The Pearson correlation coefficient was used to analyze the correlation between ficolins and pyroptosis- and NET-related markers in clinical samples. In this study, ficolin-2 (similar to ficolin-A) showed significant overexpression in patients with acute respiratory distress syndrome. In vivo, knockout of Fcna, but not Fcnb, attenuated lung inflammation and inhibited NET formation in the LPS-induced mouse model. DNase I further alleviated lung inflammation and NET formation in Fcna knockout mice. In vitro, neutrophils derived from Fcna-/- mice showed less pyroptosis and necroptosis than those from the control group after LPS stimulation. Additionally, GSDMD knockdown or Nod-like receptor protein 3 inhibitor reduced NET formation. Addition of recombinant ficolin-2 protein to human peripheral blood neutrophils promoted NET formation and pyroptosis after LPS stimulation, whereas Fcn2 knockdown had the opposite effect. Acute respiratory distress syndrome patients showed increased levels of pyroptosis- and NET-related markers, which were correlated positively with ficolin-2 levels. In conclusion, these results suggested that ficolin-A/2 exacerbated NET formation and LPS-induced lung injury via gasdermin D-mediated pyroptosis.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Trampas Extracelulares
/
Piroptosis
/
Ficolinas
/
Neutrófilos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Am J Pathol
Año:
2024
Tipo del documento:
Article
País de afiliación:
China